JP4676448B2 - Proteolytic enzyme inhibitor enhancement agent and skin moisture retention improver containing the same - Google Patents
Proteolytic enzyme inhibitor enhancement agent and skin moisture retention improver containing the same Download PDFInfo
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- JP4676448B2 JP4676448B2 JP2007011737A JP2007011737A JP4676448B2 JP 4676448 B2 JP4676448 B2 JP 4676448B2 JP 2007011737 A JP2007011737 A JP 2007011737A JP 2007011737 A JP2007011737 A JP 2007011737A JP 4676448 B2 JP4676448 B2 JP 4676448B2
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- cystatin
- inhibitor
- collagen
- skin
- proteolytic enzyme
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Description
本発明は、皮膚においてタンパク質分解酵素阻害因子を増加させ、またはタンパク質分解酵素阻害因子の発現を増強させることにより、タンパク質分解酵素とタンパク質分解酵素阻害因子のバランスを制御し、皮膚の保水率を改善させる組成物に関する。特に、本発明は、コラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物又はコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分として含む皮膚の保水率改善剤、又はシスタチン等のタンパク質分解酵素阻害因子を有効成分として含む皮膚の保水率改善剤に関する。 The present invention controls the balance between proteolytic enzyme and proteolytic enzyme inhibitory factor by increasing the proteolytic enzyme inhibitory factor in the skin or enhancing the expression of the proteolytic enzyme inhibitory factor, thereby improving the water retention rate of the skin It is related with the composition made to make. In particular, the present invention relates to a skin water retention rate improving agent or a proteolytic enzyme such as cystatin, which contains, as an active ingredient, collagen or a degradation product of collagen in which collagen synthesis is promoted in vivo or an amino acid composition close to the amino acid composition of collagen. The present invention relates to a skin water retention rate improving agent comprising an inhibitory factor as an active ingredient.
誰もが、いくつになっても元気に暮らしたいと願っている。しかし、老化に伴う生理的変化のアンバランスは、ホルモン分泌の低下、酸化ストレスや免疫力の低下によって引起され認知症や骨粗鬆症のような代表的な疾病を引起す。皮膚については加齢に伴う老化によって、皮膚のたるみ、しわ、乾燥などの変化を認め、紫外線を浴びることによってしわが形成されたり色素が沈着したりといった好ましくない変化が観察される。 Everyone wants to live well no matter how many. However, the unbalance of physiological changes associated with aging is caused by a decrease in hormone secretion, oxidative stress and a decrease in immunity, and causes typical diseases such as dementia and osteoporosis. With regard to the skin, changes such as sagging, wrinkles, and dryness are observed due to aging with aging, and undesirable changes such as formation of wrinkles and pigmentation are observed when exposed to ultraviolet rays.
皮膚の最外層は角層で形成され、その厚さが僅か20μmほどの構造で、表皮角化細胞から分化した角層細胞とその細胞間に充満する細胞間脂質からなる。その構造は、ブロックとモルタルにたとえられる。ブロックに相当する角層細胞は、表皮角化細胞の分化により形成される。その成分の大半（約80％）はケラチン繊維で、共存する水分により角層全体の物理化学的性質を左右している。一方、モルタルに相当する細胞間脂質は、コレステロール、コレステロールエステル、脂肪酸、セラミドを主成分とし、ラメラ構造（層状構造）を形成することで角層のバリア機能に深く関わっている。ブロックを包みモルタルとの界面を形成するコーニファイドエンベロープ（角化肥厚膜）も角層バリア機能の形成に重要な役割を担っていることが明らかにされてきている。 The outermost layer of the skin is formed by the stratum corneum, and has a thickness of only about 20 μm, and is composed of stratum corneum cells differentiated from epidermal keratinocytes and intercellular lipids filled between the cells. Its structure is likened to blocks and mortar. Corneal cells corresponding to blocks are formed by the differentiation of epidermal keratinocytes. Most of the components (about 80%) are keratin fibers, and the coexisting moisture affects the physicochemical properties of the entire stratum corneum. On the other hand, intercellular lipids corresponding to mortar are mainly related to cholesterol, cholesterol ester, fatty acid, and ceramide, and have a lamellar structure (layered structure) to deeply relate to the barrier function of the stratum corneum. It has been clarified that a confined envelope (keratinized thickened film) that wraps blocks and forms an interface with mortar also plays an important role in the formation of the stratum corneum barrier function.
角層は表皮のターンオーバーによって絶えず生まれ変わっている。最外層の角層細胞は、通常感知されずに順次剥がれ落ちてゆく。剥がれ落ちるまでの角層細胞は、コーネオデスモゾーム(corneodesmosome)と呼ばれるタンパク質複合体からなる接着装置を介して、お互いに接着している。従って、皮膚を擦っても角層が剥がれ落ちてしまうことはない。角層の最外層にかけて、コーネオデスモソームを構成するタンパク質（デスモグレイン、デスモコリン、コーネオデスモシンなど）が幾つかのプロテアーゼによって消化されることが、円滑な角層の剥離に重要であると考えられている。 The stratum corneum is constantly being reborn by the turnover of the epidermis. The outermost stratum corneum cells usually fall off without being detected. The stratum corneum cells until they are peeled off adhere to each other through an adhesion device composed of a protein complex called corneodesmosome. Therefore, the stratum corneum does not peel off even when the skin is rubbed. It is thought that it is important for smooth exfoliation of the stratum corneum that the protein (desmoglein, desmocollin, corneodesmosine, etc.) constituting the coneeodesmosome is digested by some proteases on the outermost layer of the stratum corneum. It has been.
角層の水分を維持するメカニズムとして、皮脂層の閉塞効果、細胞間脂質のバリア機能、天然保湿因子による水分保持を挙げることができる。 Examples of the mechanism for maintaining the moisture in the stratum corneum include the occlusion effect of the sebum layer, the barrier function of intercellular lipids, and the moisture retention by natural moisturizing factors.
コーニファイドエンベロープ(cornified envelope: CE)は、インボルクリン、ロリクリンなどの前駆タンパク質がトランスグルタミナーゼにより架橋されて形成される非常に堅牢な膜状のアセンブリーで、更に脂質による修飾を受けて疎水性を獲得し、それを足場として細胞間脂質が整然と配向することによってきちんとした角層バリア機能が形成される。 The cornified envelope (CE) is a very robust membrane-like assembly formed by crosslinking precursor proteins such as involucrin and loricrin with transglutaminase. A neat stratum corneum barrier function is formed by orderly orientation of intercellular lipids using it as a scaffold.
CEを構成する前駆体タンパク質には、インボルクリン、ロリクリン、small proline rich protein(SPR、cornifin)、シスタチンA、エラフィン、フィラグリン、ケラチン、エンボプラキン、デスモソーム構成タンパク質、スキエリン、アネキシンI、PAI−２などが挙げられる。これらは、表皮ケラチノサイトの分化に従って有棘層上層から顆粒層にかけて発現する。そして角層に到る過程で、これらのタンパク質のリシン残基とグルタミン残基との間にイソペプチド結合が形成されることによって、架橋・不溶化し、CEができあがる。また、グルタミン残基同士がポリアミンの介在によって形成されるシュードイソペプチド結合の存在も知られている。これらの結合の形成は、表皮ケラチノサイトの分化に伴って産生される酵素トランスグルタミナーゼ(TGase)により触媒される（非特許文献１を参照）。 Precursor proteins constituting CE include involucrin, loricrin, small proline rich protein (SPR, cornifin), cystatin A, elafin, filaggrin, keratin, emboplatin, desmosome constituent protein, schielin, annexin I, PAI-2, etc. It is done. These are expressed from the upper spinous layer to the granular layer according to the differentiation of epidermal keratinocytes. In the process of reaching the stratum corneum, an isopeptide bond is formed between the lysine residue and the glutamine residue of these proteins, thereby cross-linking and insolubilizing and producing CE. In addition, existence of a pseudoisopeptide bond in which glutamine residues are formed by the interposition of polyamine is also known. The formation of these bonds is catalyzed by the enzyme transglutaminase (TGase) produced with the differentiation of epidermal keratinocytes (see Non-Patent Document 1).
シスタチンのサブタイプのひとつCst6のnullノックアウトマウスは、皮膚においてケラチナイゼーションが不全となるヒトのハーレクインイクチオーシスという遺伝病のマウスモデルichqマウスとして報告されている(非特許文献２を参照)。該モデルマウスのフェノタイプの解析により、システインプロテアーゼ阻害因子シスタチンM/E（Cst6の遺伝子産物）を欠損させることによって角層不全が起こり、バリアー機能が低下して脱水死することが判っている。シスタチンM/Eのnullノックアウトマウスは、皮膚蒸散量をTEWL(Transepidermal Water Loss)によって測定した結果、出生9日目までTEWLが増加し続け、3g/m2/hに到達した。6〜9日目あたりから体重は急激に減少し、11日目に脱水が原因で死亡した。従って、シスタチンが皮膚における角層の健全な形成に重要である可能性が示唆されている。非特許文献２においては、皮膚においてタンパク質分解酵素とその阻害因子の絶妙なバランスが健康な角層に必須であり、ちょうど、外界と生体の境界域で非特異的免疫機能を担うタンパク質分解酵素と、過剰な非特異的免疫のブレーキ役であるタンパク質分解酵素阻害因子がせめぎあっていると表現されている。
A null knockout mouse of
本発明は、皮膚におけるタンパク質分解酵素の阻害因子を増加させる組成物の提供を目的とし、該組成物は皮膚の保水率の改善をもたらす。 The present invention is directed to providing a composition that increases the inhibitor of proteolytic enzymes in the skin, which composition provides improved skin water retention.
上記のように、遺伝子のnull欠損マウスの解析結果よりタンパク質分解酵素の阻害因子が皮膚における角層の形成において重要であることが示唆されていた。しかし、皮膚におけるこれらの阻害因子の増加が本当に皮膚の保水率の改善をもたらすのかは明確ではなかった。 As described above, the analysis results of the gene null- deficient mice suggested that the protease inhibitor is important in the formation of the stratum corneum in the skin. However, it was not clear whether an increase in these inhibitors in the skin really resulted in an improvement in the water retention rate of the skin.
本発明者らは、シスタチン等のタンパク質分解酵素の阻害因子と皮膚の保水率の変動について鋭意検討を行なった。その結果、シスタチン等のタンパク質分解酵素の阻害因子を経口投与することにより、皮膚の保水性が改善されることを見出した。 The inventors of the present invention have made extensive studies on changes in the inhibitor of proteolytic enzymes such as cystatin and the water retention rate of the skin. As a result, it was found that the water retention of the skin was improved by orally administering an inhibitor of proteolytic enzymes such as cystatin.
本発明者らは、さらにシスタチンA遺伝子の転写調節部位がAP2配列やPKC（プロテインキナーゼC）に応答する配列を有し、このうちPKCはコラーゲン繊維によって活性化されるという報告(JCB '97, 136, 2, 473-483)に鑑み、コラーゲンとシスタチンとの関連に注目した。本発明者等は、ウエスタンブロッティングによるタンパク質レベルにおいて、また、ジーンチップの解析によるRNAレベルにおいて、コラーゲンの摂取がシスタチンAの発現を増強し、皮膚の保水率を改善することを見出した。本発明者等は、コラーゲンの摂取によって皮膚に基質的な何らかの変化が引き起こされ、皮膚コラーゲンの３次元構造がリジッドとなるなど繊維状態が改善され、これによってPKCの活性化が惹起されて、シスタチン遺伝子の転写が活発になり、さらにシスタチンタンパク質の増加が引き起こされたと考えた。すなわち、コラーゲンが皮膚における非特異的防御機構とその阻害因子のバランスに対し、阻害因子（シスタチン）を補強することによって保水率を増加させることを見出し、本発明を完成させるに至った。 The present inventors further reported that the transcriptional regulatory site of the cystatin A gene has a sequence that responds to the AP2 sequence and PKC (protein kinase C), among which PKC is activated by collagen fibers (JCB '97, 136, 2, 473-483), we focused on the relationship between collagen and cystatin. The present inventors have found that the intake of collagen enhances the expression of cystatin A and improves the water retention rate of the skin at the protein level by Western blotting and at the RNA level by gene chip analysis. The inventors of the present invention have suggested that the ingestion of collagen causes some substrate-like changes in the skin, and the fiber state is improved such that the three-dimensional structure of skin collagen becomes rigid, thereby inducing activation of PKC and causing cystatin. It was thought that gene transcription became active and cystatin protein increased. That is, collagen was found to increase the water retention rate by reinforcing the inhibitor (cystatin) against the balance between the non-specific defense mechanism and the inhibitor in the skin, and the present invention was completed.
すなわち、本発明は以下のとおりである。
[１] コラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物若しくはコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分として含むタンパク質分解酵素阻害因子発現増強剤。
[２] グリシン30〜40％、プロリン10〜20％、ヒドロキシプロリン7.5〜15％、アラニン7.5〜15％を含むアミノ酸組成からなる組成物を有効成分として含む[１]のタンパク質分解酵素阻害因子発現増強剤。
That is, the present invention is as follows.
[1] A proteolytic enzyme inhibitor enhancement agent comprising, as an active ingredient, collagen or a degradation product of collagen in which collagen synthesis is promoted in vivo or an amino acid composition close to the amino acid composition of collagen.
[2] Proteolytic enzyme inhibitor expression of [1] comprising an amino acid composition comprising 30-40% glycine, 10-20% proline, 7.5-15% hydroxyproline, 7.5-15% alanine as an active ingredient Enhancer.
[３] タンパク質分解酵素阻害因子が、ステフィンA1、シスタチンα、ステフィンA2、ステフィン2様、シスタチンC、シスタチンN(6)、シスタチンS、シスタチンTE-1、シスタチン8、シスタチン11、シスタチンB、シスタチン関連2、CSTA、シスタチンA、シスタチンM/E、１型プラスミノーゲン活性化因子阻害剤、2型プラスミノーゲン活性化因子阻害剤、C1阻害剤（SERPING１）、セリンプロテアーゼ阻害剤（Kazal型５）、セリンプロテアーゼ阻害剤（Kazal型４）（SPINK４）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー６）（SERPINB６）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー７）（SERPINB７）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー５）（SERPINB５）、プロテアーゼ阻害剤（KladeB[オボアルブミン]）（メンバー９）、サイクリン依存性キナーゼ阻害剤２C(Cdkn2c)、サイクリン依存性キナーゼ阻害剤２A(Cdkn2a)、サイクリン依存性キナーゼ阻害剤２B（ｐ１５、CDK４を阻害する）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeE[ネキシン、１型プラスミノーゲン活性化因子阻害剤]）（メンバー）（SERPINE１）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeE）（メンバー２）（SERPINE２）、メタロプロテアーゼ２組織阻害因子（Timp2）、メタロプロテアーゼ１組織阻害因子（Timp１）、組織因子経路阻害剤（TFPI）、組織因子経路阻害剤２（TFPI２）及びカテプシンF（CTSF）からなる群から選択される[１]又は[２]のタンパク質分解酵素阻害因子発現増強剤。
[3] Proteolytic enzyme inhibitors are Stefin A1, Cystatin α, Stefin A2, Stefin 2-like, Cystatin C, Cystatin N (6), Cystatin S, Cystatin TE-1, Cystatin 8, Cystatin 11, Cystatin B, Cystatin Related 2, CSTA, cystatin A, cystatin M / E,
[４] タンパク質分解酵素阻害因子が、ステフィンA1、シスタチンα、ステフィンA2、ステフィン2様、シスタチンC、シスタチンN(6)、シスタチンS、シスタチンTE-1、シスタチン8、シスタチン11、シスタチンB、シスタチン関連2、CSTA、シスタチンA及びシスタチンM/Eからなる群から選択されるタンパク質分解酵素阻害因子である[３]のタンパク質分解酵素阻害因子発現増強剤。
[５] [１]〜[４]のいずれかのタンパク質分解酵素阻害因子発現増強剤を含む皮膚の保水率改善剤。
[６] [１]〜[４]のいずれかのタンパク質分解酵素阻害因子発現増強剤を含む食品。
[７] 皮膚の保水率を改善するものである旨の表示を付した、[６]の食品。
[８] [１]〜[４]のいずれかのタンパク質分解酵素阻害因子発現増強剤を含む化粧品。
[９] [１]〜[４]のいずれかのタンパク質分解酵素阻害因子発現増強剤を含む医薬組成物。
[4] Proteolytic enzyme inhibitors are Stefin A1, Cystatin α, Stefin A2, Stefin 2-like, Cystatin C, Cystatin N (6), Cystatin S, Cystatin TE-1, Cystatin 8, Cystatin 11, Cystatin B, Cystatin [2] The proteolytic enzyme inhibitor enhancement agent of [3], which is a proteolytic enzyme inhibitor selected from the group consisting of Related 2, CSTA, cystatin A and cystatin M / E.
[5] A skin water retention rate improving agent comprising the proteolytic enzyme inhibitor enhancement agent according to any one of [1] to [4].
[6] A food containing the proteolytic enzyme inhibitor enhancing agent of any one of [1] to [4].
[7] The food according to [6], which is labeled as improving the moisture retention rate of the skin.
[8] A cosmetic comprising the proteolytic enzyme inhibitor enhancement agent of any one of [1] to [4].
[9] A pharmaceutical composition comprising the proteolytic enzyme inhibitor enhancer expression enhancer according to any one of [1] to [4].
[１０] ステフィンA1、シスタチンα、ステフィンA2、ステフィン2様、シスタチンC、シスタチンN(6)、シスタチンS、シスタチンTE-1、シスタチン8、シスタチン11、シスタチンB、シスタチン関連2、CSTA、シスタチンA、シスタチンM/E、１型プラスミノーゲン活性化因子阻害剤、2型プラスミノーゲン活性化因子阻害剤、C1阻害剤（SERPING１）、セリンプロテアーゼ阻害剤（Kazal型５）、セリンプロテアーゼ阻害剤（Kazal型４）（SPINK４）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー６）（SERPINB６）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー７）（SERPINB７）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー５）（SERPINB５）、プロテアーゼ阻害剤（KladeB[オボアルブミン]）（メンバー９）、サイクリン依存性キナーゼ阻害剤２C(Cdkn2c)、サイクリン依存性キナーゼ阻害剤２A(Cdkn2a)、サイクリン依存性キナーゼ阻害剤２B（ｐ１５、CDK４を阻害する）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeE[ネキシン、１型プラスミノーゲン活性化因子阻害剤]）（メンバー）（SERPINE１）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeE）（メンバー２）（SERPINE２）、メタロプロテアーゼ２組織阻害因子（Timp2）、メタロプロテアーゼ１組織阻害因子（Timp１）、組織因子経路阻害剤（TFPI）、組織因子経路阻害剤２（TFPI２）及びカテプシンF（CTSF）からなる群から選択されるタンパク質分解酵素阻害因子を有効成分として含む皮膚の保水率改善剤。
[10] Stefin A1, Cystatin α, Stefin A2, Stefin 2-like, Cystatin C, Cystatin N (6), Cystatin S, Cystatin TE-1, Cystatin 8, Cystatin 11, Cystatin B, Cystatin related 2, CSTA, Cystatin A , Cystatin M / E,
[１１] ステフィンA1、シスタチンα、ステフィンA2、ステフィン2様、シスタチンC、シスタチンN(6)、シスタチンS、シスタチンTE-1、シスタチン8、シスタチン11、シスタチンB、シスタチン関連2、CSTA、シスタチンA及びシスタチンM/Eからなる群から選択されるタンパク質分解酵素阻害因子を含む[１０]の皮膚の保水率改善剤。
[１２] [１０]又は[１１]の皮膚の保水率改善剤を含む食品。
[１３] 皮膚の保水率を改善するものである旨の表示を付した、[１２]の食品。
[１４] [１０]又は[１１]の皮膚の保水率改善剤を含む化粧品。
[１５] [１０]又は[１１]の皮膚の保水率改善剤を含む医薬組成物。
[11] Stefin A1, Cystatin α, Stefin A2, Stefin 2-like, Cystatin C, Cystatin N (6), Cystatin S, Cystatin TE-1, Cystatin 8, Cystatin 11, Cystatin B, Cystatin related 2, CSTA, Cystatin A And [10] a skin water retention rate improving agent comprising a proteolytic enzyme inhibitor selected from the group consisting of cystatin M / E.
[12] A food comprising the skin moisture retention improving agent according to [10] or [11].
[13] The food according to [12], which is labeled as improving the moisture retention rate of the skin.
[14] A cosmetic comprising the skin moisture retention improving agent according to [10] or [11].
[15] A pharmaceutical composition comprising the skin water retention rate improving agent of [10] or [11].
コラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物又はコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分として含むタンパク質分解酵素阻害因子発現増強剤、あるいはシスタチン等のタンパク質分解酵素阻害因子をヒトに投与することにより、皮膚におけるタンパク質分解酵素阻害因子の存在量が増大し、皮膚のタンパク質分解酵素とその阻害因子のバランスが制御され、皮膚の各層の形成が良好になり、皮膚の保水率が改善される。 Proteolytic enzyme inhibitor expression enhancer containing collagen or a degradation product of collagen that promotes collagen synthesis in vivo or an amino acid composition close to the amino acid composition of collagen as an active ingredient, or a proteolytic enzyme inhibitor such as cystatin To increase the abundance of proteolytic enzyme inhibitors in the skin, control the balance of skin proteolytic enzymes and their inhibitors, improve the formation of each layer of the skin, and increase the water retention rate of the skin Improved.
以下、本発明を詳細に説明する。
本発明で用い得るコラーゲンの種類に限定はなく、I型コラーゲンからVIII型コラーゲンまで広く用いることができる。ここで、I型コラーゲンは、骨や皮膚の真皮に大量に含まれる線維性コラーゲンをいう。I型コラーゲンは、α1鎖（I型）2本とα2鎖（I型）1本が集まって形成される。II型コラーゲンは、軟骨に主に含まれる線維性コラーゲンをいい、３本のα1（II型）鎖から構成される。III型コラーゲンは、細胞などの足場を形成している線維性コラーゲンをいう。IV型コラーゲンは、基底膜に多く含まれる非線維性コラーゲンをいう。V型コラーゲンは、α1（V型）鎖、α2（V型）鎖、α3（V型）鎖が様々な割合で混合した三量体の混合物である線維性コラーゲンである。VI型コラーゲンは、α鎖が2本逆向きに会合したものが2つ集まった四量体を形成する非線維性コラーゲンである。VII型コラーゲンは、IV型コラーゲン同様、基底膜の構成成分であり、三量体を形成する非線維性コラーゲンである。VIII型コラーゲンは、血管内皮細胞を形成する非線維性コラーゲンである。
Hereinafter, the present invention will be described in detail.
There is no limitation on the type of collagen that can be used in the present invention, and a wide range of types can be used from type I collagen to type VIII collagen. Here, type I collagen refers to fibrous collagen contained in large amounts in the dermis of bones and skin. Type I collagen is formed by collecting two α1 chains (type I) and one α2 chain (type I). Type II collagen is fibrous collagen mainly contained in cartilage, and is composed of three α1 (type II) chains. Type III collagen refers to fibrous collagen that forms a scaffold such as cells. Type IV collagen refers to non-fibrous collagen that is abundant in the basement membrane. Type V collagen is fibrous collagen that is a mixture of trimers in which α1 (V type) chain, α2 (V type) chain, and α3 (V type) chain are mixed at various ratios. Type VI collagen is a non-fibrous collagen that forms a tetramer in which two α chains are assembled in the opposite direction. Like type IV collagen, type VII collagen is a non-fibrous collagen that is a constituent of the basement membrane and forms a trimer. Type VIII collagen is a non-fibrous collagen that forms vascular endothelial cells.
本発明においてコラーゲン源としては、コラーゲンの原料として使用できるものであれば特に限定はしないが、例えば哺乳動物の皮、骨、鳥類の軟骨や骨、魚類の軟骨や骨、皮、鱗などを使用することができる。この中でも特に、魚類の軟骨、骨、皮及び鱗等の魚類原料が好ましい。また、本発明においては、一度抽出されたコラーゲン含有物や市販のコラーゲンも含まれる。 In the present invention, the collagen source is not particularly limited as long as it can be used as a collagen raw material. For example, mammalian skin, bone, avian cartilage or bone, fish cartilage or bone, skin, scale, etc. are used. can do. Among these, fish raw materials such as fish cartilage, bone, skin and scale are particularly preferable. Moreover, in this invention, the collagen containing material extracted once and commercially available collagen are also contained.
前抽出や前処理の方法は特に限定はないが、単なる水洗、焙煎、蒸しなどを通常の方法に従って行ってもよく、プロテアーゼ処理を行ってもよく、また、これらを組み合わせて行うこともできる。前処理後のコラーゲン源の形状としては特に限定はないが、粉状、フレーク状、細状、薄片、角切り、又はそのままで使用すればよい。 The method of pre-extraction or pre-treatment is not particularly limited, but simple washing, roasting, steaming, etc. may be performed according to ordinary methods, protease treatment may be performed, or a combination of these may be performed. . The shape of the collagen source after the pretreatment is not particularly limited, but it may be used in the form of powder, flakes, fines, flakes, chops, or as they are.
コラーゲンの分解物として、コラーゲンの酸分解物、アルカリ分解物、熱分解物、酵素分解物等があり、ゼラチン及びコラーゲンペプチドが挙げられる。コラーゲンペプチドとは、コラーゲンを加水分解して得られるペプチドであり、本発明の組成物に用い得るコラーゲンペプチドの平均分子量は例えばゲルクロマトグラフィーにより測定した場合200〜15,000、好ましくは200〜1500、さらに、好ましくは500〜1000である。また、これより分子量の小さいジペプチドなどの低分子量成分が一部に含まれていてもよい。好ましくは、上記の分子量のコラーゲンペプチドが70％以上、さらに好ましくは80％以上、特に好ましくは90％以上含まれる。ゼラチンは、コラーゲンを加熱し、又は塩酸や硫酸等の無機酸や石灰等のアルカリを用いて処理することにより得られる。コラーゲンペプチドは、コラーゲン又はゼラチンをコラゲナーゼ、システインプロテアーゼ等のタンパク質分解酵素で処理することにより得られる。 Examples of collagen degradation products include collagen acid degradation products, alkali degradation products, thermal degradation products, enzyme degradation products, and the like, and examples include gelatin and collagen peptides. The collagen peptide is a peptide obtained by hydrolyzing collagen, and the average molecular weight of the collagen peptide that can be used in the composition of the present invention is, for example, 200 to 15,000, preferably 200 to 1500, as measured by gel chromatography. Preferably, it is 500-1000. In addition, a low molecular weight component such as a dipeptide having a smaller molecular weight may be included in part. Preferably, the collagen peptide having the above molecular weight is contained in an amount of 70% or more, more preferably 80% or more, and particularly preferably 90% or more. Gelatin can be obtained by heating collagen or treating it with an inorganic acid such as hydrochloric acid or sulfuric acid, or an alkali such as lime. A collagen peptide is obtained by treating collagen or gelatin with a proteolytic enzyme such as collagenase or cysteine protease.
本発明の組成物はさらに、アミノ酸組成物でもよく、コラーゲンのアミノ酸組成に近似したアミノ酸組成物である。コラーゲンのアミノ酸組成はグリシンが約34％、プロリンが約13％、ヒドロキシプロリンが約９％、アラニンが約11％、その他のアミノ酸が約33％であり、トリプトファンを含まない。従って、本発明のアミノ酸からなる組成物は、グリシンが30〜40％、好ましくは33〜35％、さらに好ましくは34％、プロリンが10〜20％、好ましくは12〜14％、さらに好ましくは13％、ヒドロキシプロリンが7.5〜15％、好ましくは８〜10％、さらに好ましくは９％、アラニンが7.5〜15％、好ましくは10〜12％、さらに好ましくは11％含まれるアミノ酸組成物であり、トリプトファン含有量は少ない。また、アルギニンはコラーゲン合成を促進するので、アルギニンを含んでいてもよい。 The composition of the present invention may further be an amino acid composition, which is an amino acid composition that approximates the amino acid composition of collagen. The amino acid composition of collagen is about 34% for glycine, about 13% for proline, about 9% for hydroxyproline, about 11% for alanine, about 33% for other amino acids, and does not contain tryptophan. Therefore, in the composition comprising the amino acid of the present invention, glycine is 30 to 40%, preferably 33 to 35%, more preferably 34%, proline is 10 to 20%, preferably 12 to 14%, more preferably 13 %, Hydroxyproline 7.5-15%, preferably 8-10%, more preferably 9%, alanine 7.5-15%, preferably 10-12%, more preferably 11% amino acid composition, Low tryptophan content. Moreover, since arginine promotes collagen synthesis, it may contain arginine.
また、コラーゲンに特徴的なアミノ酸であるヒドロキシプロリンは、プロリンのヒドロキシル化によっても生成される。プロリンのヒドロキシル化は、還元剤としてビタミンCが必要で、ビタミンCが欠乏するとコラーゲン合成に異常をきたす。従って、本発明の組成物はビタミンC又はその誘導体を含んでいてもよい。ビタミンC誘導体としてアスコルビン酸ナトリウム等が挙げられる。 Hydroxyproline, an amino acid characteristic of collagen, is also generated by hydroxylation of proline. Hydroxylation of proline requires vitamin C as a reducing agent, and deficiency in vitamin C causes abnormalities in collagen synthesis. Therefore, the composition of the present invention may contain vitamin C or a derivative thereof. Examples of vitamin C derivatives include sodium ascorbate.
本発明のコラーゲン又はコラーゲンの分解物若しくはコラーゲンのアミノ酸組成に近いアミノ酸組成物を摂取することにより、生体内でコラーゲンの合成が促進され、タンパク質分解酵素阻害因子の発現を促進する。この結果、皮膚における保水率を改善することができる。ここで、皮膚における保水率の改善とは、皮膚表面からの水分蒸発を防ぎ、皮膚における水分存在量を高め一定に保つようにすることをいう。皮膚における保水率は、例えば経皮的水分散逸量（TEWL)や皮膚のキャパシタンスにより評価することができる。TEWLは、例えばテバメーター（インテグラル）により測定することができ、キャパシタンスはコルネオメーター（皮膚水分量測定器）により測定することができる。本発明の保水率が改善された皮膚の保水率は、コルネオメーターで測定した場合、キャパシタンス値が１０以上、好ましくは３０以上である。 By ingesting the collagen of the present invention or a degradation product of collagen or an amino acid composition close to the amino acid composition of collagen, the synthesis of collagen is promoted in vivo and the expression of a protease inhibitor is promoted. As a result, the water retention rate in the skin can be improved. Here, the improvement of the water retention rate in the skin refers to preventing moisture evaporation from the skin surface and increasing the moisture content in the skin to keep it constant. The water retention rate in the skin can be evaluated by, for example, transcutaneous water dispersion loss (TEWL) or skin capacitance. TEWL can be measured by, for example, a tevameter (integral), and capacitance can be measured by a corneometer (skin moisture meter). The skin water retention rate with improved water retention rate according to the present invention has a capacitance value of 10 or more, preferably 30 or more, when measured with a corneometer.
本発明のコラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物若しくはコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分として含むタンパク質分解酵素阻害因子発現増強剤は、ステフィンA1、シスタチンα、ステフィンA2、ステフィン2様、シスタチンC、シスタチンN(6)、シスタチンS、シスタチンTE-1、シスタチン8、シスタチン11、シスタチンB、シスタチン関連2、CSTA、シスタチンA、シスタチンM/E、１型プラスミノーゲン活性化因子阻害剤、2型プラスミノーゲン活性化因子阻害剤、C1阻害剤（SERPING１）、セリンプロテアーゼ阻害剤（Kazal型５）、セリンプロテアーゼ阻害剤（Kazal型４）（SPINK４）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー６）（SERPINB６）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー７）（SERPINB７）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeB[オボアルブミン]）（メンバー５）（SERPINB５）、プロテアーゼ阻害剤（KladeB[オボアルブミン]）（メンバー９）、サイクリン依存性キナーゼ阻害剤２C(Cdkn2c)、サイクリン依存性キナーゼ阻害剤２A(Cdkn2a)、サイクリン依存性キナーゼ阻害剤２B（ｐ１５、CDK４を阻害する）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeE[ネキシン、１型プラスミノーゲン活性化因子阻害剤]）（メンバー）（SERPINE１）、セリン（またはシステイン）プロテアーゼ阻害剤（CladeE）（メンバー２）（SERPINE２）、メタロプロテアーゼ２組織阻害因子（Timp2）、メタロプロテアーゼ１組織阻害因子（Timp１）、組織因子経路阻害剤（TFPI）、組織因子経路阻害剤２（TFPI２）及びカテプシンF（CTSF）からなる群から選択されるタンパク質分解酵素阻害因子の発現を増強し得る。この中でも特に皮膚のシスタチンの発現増強に効果がある。 The proteolytic enzyme inhibitor enhancement agent comprising the collagen of the present invention or a degradation product of collagen in which collagen synthesis is promoted in vivo or an amino acid composition close to the amino acid composition of collagen as an active ingredient is stefin A1, cystatin α, stefin A2, Stefin 2-like, Cystatin C, Cystatin N (6), Cystatin S, Cystatin TE-1, Cystatin 8, Cystatin 11, Cystatin B, Cystatin related 2, CSTA, Cystatin A, Cystatin M / E, Type 1 plasmino Gene activator inhibitor, type 2 plasminogen activator inhibitor, C1 inhibitor (SERPING1), serine protease inhibitor (Kazal type 5), serine protease inhibitor (Kazal type 4) (SPINK4), serine ( Or cysteine) protease inhibitor (CladeB [ovalbumin]) (member 6) (SERPINB6), serine (also Is a cysteine) protease inhibitor (CladeB [ovalbumin]) (member 7) (SERPINB7), serine (or cysteine) protease inhibitor (CladeB [ovalbumin]) (member 5) (SERPINB5), protease inhibitor (KladeB [ Ovalbumin]) (member 9), cyclin-dependent kinase inhibitor 2C (Cdkn2c), cyclin-dependent kinase inhibitor 2A (Cdkn2a), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4), serine (or Cysteine) protease inhibitor (CladeE [nexin, type 1 plasminogen activator inhibitor]) (member) (SERPINE1), serine (or cysteine) protease inhibitor (CladeE) (member 2) (SERPINE2), metalloprotease 2 Tissue inhibitor (Timp2), Metalloprotease 1 tissue inhibitor (Timp1), Tissue factor Expression of a proteolytic enzyme inhibitor selected from the group consisting of child pathway inhibitor (TFPI), tissue factor pathway inhibitor 2 (TFPI2) and cathepsin F (CTSF) can be enhanced. Among these, it is particularly effective in enhancing the expression of cystatin in the skin.
本発明はさらに上記のタンパク質分解酵素阻害因子発現増強剤を含む皮膚の保水率改善剤を包含する。上記の中でも特にシスタチンが好ましい。 The present invention further includes a skin water retention rate improving agent comprising the above-mentioned proteolytic enzyme inhibitor enhancement agent. Of these, cystatin is particularly preferred.
上記のタンパク質分解酵素阻害因子は、植物等の天然の原料から抽出し、さらに精製して用いることができる。例えば、シスタチンは、アボガドやメロン等の植物原料から得ることができる。また、化学合成により又は遺伝子工学的に合成することもできる。 The above proteolytic enzyme inhibitor can be extracted from a natural raw material such as a plant and further used after purification. For example, cystatin can be obtained from plant materials such as avocado and melon. It can also be synthesized by chemical synthesis or by genetic engineering.
さらに、本発明は、コラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物若しくはコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分として含むタンパク質分解酵素阻害因子発現増強剤を含む皮膚の保水率改善剤を含む。該保水率改善剤は、皮膚の保水率を改善するための医薬組成物として用いることができ、さらに、皮膚の保水率を改善するための食品及び飲料として用いることができる。食品及び飲料は健康食品、特定保健用食品、栄養機能食品、栄養補助食品、サプリメント等を含む。ここで、特定保健用食品とは、食生活において特定の保健の目的で摂取をし、その摂取により当該保健の目的が期待できる旨の表示をする食品をいう。これらの飲料品には、皮膚の保水率を改善するために用いられるものである旨の表示や美容のために用いられるものである旨の表示が付されていてもよい。 Furthermore, the present invention provides a water retention rate of skin containing collagen or a degradation product of collagen that promotes collagen synthesis in vivo or an amino acid composition close to the amino acid composition of collagen as an active ingredient. Contains an improver. The water retention rate improving agent can be used as a pharmaceutical composition for improving the skin water retention rate, and can further be used as a food and beverage for improving the skin water retention rate. Foods and beverages include health foods, foods for specified health use, functional nutritional foods, nutritional supplements, supplements and the like. Here, the food for specified health refers to food that is ingested for the purpose of specific health in the diet and displays that the purpose of the health can be expected by the intake. These beverage products may have a display indicating that they are used for improving the water retention rate of the skin or a display indicating that they are used for beauty.
食品及び飲料には、限定はないが、例えば穀物加工品（小麦粉加工品、でんぷん類加工品、プレミックス加工品、麺類、マカロニ類、パン類、あん類、そば類、麩、ビーフン、はるさめ、包装餅など）、油脂加工品（可塑性油脂、てんぷら油、サラダ油、マヨネーズ類、ドレッシングなど）、大豆加工品（豆腐類、味噌、納豆など）、食肉加工品（ハム、ベーコン、プレスハム、ソーセージなど）、水産製品（冷凍すり身、かまぼこ、ちくわ、はんぺん、さつま揚げ、つみれ、すじ、魚肉ハム、ソーセージ、かつお節、魚卵加工品、水産缶詰、つくだ煮など）、乳製品（原料乳、クリーム、ヨーグルト、バター、チーズ、練乳、粉乳、アイスクリームなど）、野菜・果実加工品（ペースト類、ジャム類、漬物類、果実飲料、野菜飲料、ミックス飲料など）、菓子類（チョコレート、ビスケット類、菓子パン類、ケーキ、餅菓子、米菓類、キャンディーなど）、アルコ−ル飲料（日本酒、中国酒、ワイン、ウイスキー、焼酎、ウオッカ、ブランデー、ジン、ラム、酒、ビール、清涼アルコール飲料、果実酒、リキュールなど）、嗜好飲料（緑茶、紅茶、ウーロン茶、コーヒー、清涼飲料、乳酸飲料など）、調味料（しょうゆ、ソース、酢、みりん、ドレッシングタイプ調味料など）、缶詰・瓶詰・袋詰食品（牛飯、釜飯、赤飯、カレー、その他の各種調理済み食品）、半乾燥若しくは濃縮食品（レバーペースト、その他のスプレッド、そば・うどんの汁、濃縮スープ類など）、乾燥食品（即席麺類、即席カレー、インスタントコーヒー、粉末ジュース、粉末スープ、即席味噌汁、調理済み食品、調理済み飲料、調理済みスープなど）、冷凍食品（すき焼き、茶碗蒸し、うなぎ蒲焼、ハンバーグステーキ、シューマイ、餃子、各種スティック、フルーツカクテルなど）、固形食品・液状食品（スープなど）、香辛料などの農産・林産加工品、畜産加工品、水産加工品などが挙げられる。本発明の食品及び原料は食品原料として用いることもでき、食品原料としては、粉末を水に溶解して飲料の形態で使用してもよく、固形食品等の担体に添加して固形食品の形態で使用してもよく、この他、健康食品として粉末それ自体、あるいは他の有用成分と混合したタブレットや顆粒としても利用できる。より具体的には、液状の食品や嗜好品、例えば菓子類、粉末茶、アイスクリ−ム、ヨ−グルト、アルコール飲料、スポーツ飲料等の形態で使用してもよい。 Food and beverages are not limited, but for example, processed cereal products (processed flour products, processed starch products, premix processed products, noodles, macaroni, breads, hams, buckwheat, rice cakes, rice noodles, harusame, Packaged rice cakes), processed oils and fats (plastic oils, tempura oil, salad oil, mayonnaise, dressing, etc.), processed soybean products (tofu, miso, natto, etc.), processed meat products (ham, bacon, pressed ham, sausage, etc.) ), Marine products (frozen surimi, kamaboko, chikuwa, hanpen, sweet potato, tsumire, streaks, fish ham, sausage, bonito, processed egg products, canned fish, tuna stewed), dairy products (raw milk, cream, yogurt, butter) , Cheese, condensed milk, powdered milk, ice cream, etc.), processed vegetables and fruits (pastes, jams, pickles, fruit drinks, vegetable drinks, Mick Beverages, etc.), confectionery (chocolate, biscuits, confectionery breads, cakes, candy sweets, rice confectionery, candy, etc.), alcoholic beverages (Japanese sake, Chinese sake, wine, whiskey, shochu, vodka, brandy, gin, rum) , Liquor, beer, soft alcoholic beverages, fruit liquor, liqueur, etc., taste beverages (green tea, tea, oolong tea, coffee, soft drinks, lactic acid beverages, etc.), seasonings (soy sauce, sauce, vinegar, mirin, dressing type seasonings) ), Canned / bottled / packed foods (beef rice, kettle rice, red rice, curry, other cooked foods), semi-dried or concentrated foods (liver paste, other spreads, buckwheat noodle soup, concentrated soups) Etc.), dried food (instant noodles, instant curry, instant coffee, powdered juice, powdered soup, instant miso soup, cooking Foods, cooked beverages, cooked soups, etc.) frozen foods (sukiyaki, steamed rice bowl, eel bowls, hamburg steak, shumai, dumplings, various sticks, fruit cocktails, etc.), solid foods / liquid foods (soups, etc.), spices, etc. Processed agricultural / forestry products, processed livestock products, processed fishery products, etc. The food and raw material of the present invention can also be used as a food raw material. As a food raw material, a powder may be dissolved in water and used in the form of a beverage, or added to a carrier such as a solid food to form a solid food. In addition, it can be used as a tablet as a health food or as a tablet or granule mixed with other useful ingredients. More specifically, it may be used in the form of liquid foods and luxury goods such as confectionery, powdered tea, ice cream, yogurt, alcoholic beverages, sports drinks and the like.
上記の食品又は飲料にコラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物若しくはコラーゲンのアミノ酸組成に近いアミノ酸組成物あるいは上記のタンパク質分解酵素阻害因子を混ぜればよい。また、天然状態で上記のタンパク質分解酵素阻害因子を含んでいる植物の抽出物も本発明の食品又は飲料に包含される。これらの抽出物として、例えば、アボガドエキスやメロンエキス等が挙げられる。これらの抽出物を上記食品又は飲料に混ぜてもよいし、また該抽出物自体を食品又は飲料として利用することもできる。 The above food or beverage may be mixed with collagen, a collagen degradation product in which collagen synthesis is promoted in vivo, an amino acid composition close to the amino acid composition of collagen, or the above protease inhibitor. Moreover, the extract of the plant which contains said proteolytic enzyme inhibitor in a natural state is also included by the foodstuff or drink of this invention. Examples of these extracts include avocado extract and melon extract. These extracts may be mixed with the above food or beverage, or the extract itself can be used as a food or beverage.
本発明のコラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物若しくはコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分として含むタンパク質分解酵素因子発現増強剤、皮膚の保水率改善剤又は食品を経口摂取する際の摂取量は、限定されないが、１日当たりコラーゲン量に換算して約0.1g〜100ｇである。食品中の含有量は、限定されないが、１〜50％（w/v)である。また、本発明のタンパク質分解酵素阻害因子を有効成分として含む皮膚の保水率改善剤、皮膚の保水率改善剤又は食品を経口摂取する際の摂取量は、限定されないが、１日当たりタンパク質分解酵素阻害因子量で約0.1g〜100ｇである。食品中の含有量は、限定されないが、１〜50％（w/v)である。 Proteolytic enzyme factor expression enhancer, skin moisture retention improver or food containing collagen of the present invention or collagen degradation product in which collagen synthesis is promoted in vivo or an amino acid composition close to the amino acid composition of collagen as an active ingredient The amount of intake when taken orally is not limited, but is about 0.1 to 100 g in terms of the amount of collagen per day. The content in the food is not limited, but is 1 to 50% (w / v). In addition, the intake amount when orally ingesting the skin water retention rate improving agent, skin water retention rate improvement agent or food containing the proteolytic enzyme inhibitor of the present invention as an active ingredient is not limited. The amount of factor is about 0.1 to 100 g. The content in the food is not limited, but is 1 to 50% (w / v).
本発明の皮膚の保水率を改善するための医薬組成物は、公知の医薬用担体と組み合わせて製剤化すればよい。当該製剤の製造は一般的には、コラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物若しくはコラーゲンのアミノ酸組成に近いアミノ酸組成物あるいは上記のタンパク質分解酵素阻害因子等の皮膚シスタチンを増加させる作用を有する有効成分の治療上有効な量を薬理学的に許容できる液状又は固形状の担体と配合し、かつ、必要に応じて溶剤、分散剤、乳化剤、緩衝剤、安定剤、賦形剤、結合剤、崩壊剤、潤沢剤などを加えて、錠剤、顆粒剤、散剤、粉末剤、カプセル剤等の固形剤、通常液剤、懸濁剤、乳剤、軟膏剤、注射剤、塗布剤、経皮吸収剤、局所徐放剤等の液剤とすることができる。また、乾燥品でもよく、該乾燥品は使用前に適当な担体を添加することによって液状に復元することができる。本発明の医薬組成物の剤形は、投与方法によって適宜設定することができる。投与方法に特に制限はなく、経口、皮膚への直接塗布、散布、注射、噴霧または、皮膚（表皮、真皮）、皮下組織等の他の部位を介しての浸透ないし拡散に基づく物理的接触等の、公知の手段を用いることが可能である。好ましくは皮膚の保水率が低下している部位に局所的に投与する。治療上有効な量は限定されないが、望ましい用量及び投与形態を考慮に入れて決定される。例えば製剤中の有効な量は、約0.1mg/mL〜約1000mg/mLである。また、本発明の医薬組成物は、老人の乾皮症、小児の乾燥性皮膚、さめ肌、手指のあれ、ひじ、ひざ、かかと、くるぶし等の角化症の治療又は予防に用いることができる。 The pharmaceutical composition for improving the water retention rate of the skin of the present invention may be formulated in combination with a known pharmaceutical carrier. The preparation of the preparation generally increases collagen or a degradation product of collagen in which collagen synthesis is promoted in vivo, an amino acid composition close to the amino acid composition of collagen, or skin cystatin such as the above-mentioned protease inhibitor. A therapeutically effective amount of an active ingredient having an action is blended with a pharmacologically acceptable liquid or solid carrier, and if necessary, a solvent, a dispersant, an emulsifier, a buffer, a stabilizer, an excipient. , Binders, disintegrants, lubricants, etc., solids such as tablets, granules, powders, powders, capsules, etc., ordinary solutions, suspensions, emulsions, ointments, injections, coatings, It can be set as liquid agents, such as a skin absorbent and a local sustained release agent. Moreover, a dry product may be sufficient and this dry product can be decompress | restored to a liquid state by adding a suitable support | carrier before use. The dosage form of the pharmaceutical composition of the present invention can be appropriately set depending on the administration method. There are no particular restrictions on the administration method, and oral, direct application to the skin, spraying, injection, spraying, or physical contact based on penetration or diffusion through other parts such as skin (epidermis, dermis), subcutaneous tissue, etc. It is possible to use known means. Preferably, it is locally administered to a site where the water retention rate of the skin is lowered. The therapeutically effective amount is not limited, but is determined taking into account the desired dose and dosage form. For example, an effective amount in a formulation is from about 0.1 mg / mL to about 1000 mg / mL. In addition, the pharmaceutical composition of the present invention can be used for the treatment or prevention of keratosis such as dry skin of the elderly, dry skin of children, shark skin, fingertips, elbows, knees, heels, and ankles. .
本発明の化粧料は公知の配合に準じて定法に従って製造することができる。本発明の化粧料としては、例えばローション類、乳液類、クリーム類、パック類、浴用剤、洗顔剤、浴用石鹸又は浴用洗剤などを含有するものである。本発明の化粧料をそれぞれの用途形態に応じて所望の量、例えばローション類であれば、例えばヒトの顔面全体に適用するような適用法が考えられる。また、アルギン酸、ヒアルロン酸、コンドロイチン硫酸、デルマタン硫酸、ヘパラン硫酸、ヘパリン及びケラタン硫酸等のムコ多糖類などの保湿剤を含んでいてもよい。本発明の化粧料は化粧品原料として用いることもでき、化粧品原料としては、溶液製剤（防腐剤、溶剤添加の溶液）としてシャンプー、リンス、ヘアトリートメントに配合、粉末で入浴剤に配合する等、インバス製品やヘアケアアウトバス製品へ利用することができる。 The cosmetic of the present invention can be produced according to a conventional method according to a known formulation. The cosmetic of the present invention contains, for example, lotions, emulsions, creams, packs, bath preparations, facial cleansers, bath soaps or bath detergents. If the cosmetic of the present invention is in a desired amount, for example, a lotion according to each application form, an application method may be considered in which it is applied to the entire human face, for example. Further, it may contain a humectant such as mucopolysaccharides such as alginic acid, hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin and keratan sulfate. The cosmetic of the present invention can also be used as a cosmetic raw material. As a cosmetic raw material, it is incorporated into shampoos, rinses, hair treatments as solution preparations (preservatives, solvent-added solutions), and in a bath preparation as a powder. It can be used for products and hair care out bath products.
本発明の化粧品は、皮膚における保水率を改善し、皮膚の弾力やみずみずしさを保つ作用を発揮し得る。 The cosmetic of the present invention can improve the water retention rate in the skin, and can exhibit the effect of maintaining the elasticity and freshness of the skin.
本発明のコラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物又はコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分としてタンパク質分解酵素阻害因子発現増強剤、皮膚の保水率改善剤を化粧料として用いる場合の含有量は、限定されないが、例えば、0.1％〜50％（w/v)である。 As an active ingredient, the collagen of the present invention or a degradation product of collagen in which collagen synthesis is promoted in vivo or an amino acid composition close to the amino acid composition of collagen is used as an active ingredient. Although content when using as is not limited, For example, they are 0.1%-50% (w / v).
本発明を以下の実施例によって具体的に説明するが、本発明はこれらの実施例によって限定されるものではない。
実施例１ コラーゲン投与により発現が変動する遺伝子の検討
ヘアレスラット雄性HWY系（SPF、4週齢）を用い、飼育した。
The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
Example 1 Examination of genes whose expression fluctuates by collagen administration Hairless rat male HWY strain (SPF, 4 weeks old) was used for breeding.
フィッシュコラーゲンWP（マルハ（株））を5%となるようにラット用飼料CRF-1に配合した。試験飼料はオリエンタル酵母（株）に依頼して作成した（表１）。試験に用いた群構成を表２に示す。試験プロトコールを図１に示す。 Fish collagen WP (Maruha Co., Ltd.) was added to the rat feed CRF-1 so as to be 5%. The test feed was prepared by requesting Oriental Yeast Co., Ltd. (Table 1). Table 2 shows the group structure used in the test. The test protocol is shown in FIG.
皮膚の剥離
ネンブタール麻酔下（大日本製薬）、腹大動脈より採血したヘアレスラットの首周辺の背側皮膚を、速やかに外科用メスで3〜4cm四方の大きさに切り出した。皮膚に付着した筋肉を外科用メスで除去した後、6個に分割した。RNA安定化溶液(RNA later、Ambion)30mlを注いだファルコンチューブに皮膚切片を加え、冷蔵下で一晩安定化させた。翌日、個体毎にビニール袋に入替え-20℃で凍結保存した。作業はRNaseのコンタミを防ぐため、帽子、マスク、及びビニール手袋を着用した上、できる限り速やかに行った。
Skin exfoliation Under Nembutal anesthesia (Dainippon Pharmaceutical Co., Ltd.), the dorsal skin around the neck of hairless rats collected from the abdominal aorta was quickly cut into a 3-4 cm square with a scalpel. The muscle adhering to the skin was removed with a scalpel and then divided into 6 pieces. Skin sections were added to a falcon tube poured with 30 ml of RNA stabilization solution (RNA later, Ambion) and stabilized overnight under refrigeration. The next day, each individual was replaced with a plastic bag and stored frozen at -20 ° C. To prevent RNase contamination, the work was performed as quickly as possible while wearing a hat, mask, and vinyl gloves.
皮膚の破砕
皮膚の破砕はホモジナイザーAM-9（日本精機）を用い液体窒素で凍結しながら実施した。サンプルが触れるカップ内面とカッターはRNase洗浄剤(RNaseZAP、Ambion)を噴霧した後キムタオルで拭取った。液体窒素は（コンタミ源とならないよう、）サンプルと直接接触させないように注意した。30分程度のホモジナイズ中、サンプルカップの低温を保つため適宜液体窒素を補充した。ホモジナイズ操作は全てクリーンベンチ内でビニール手袋を着用して実施し、RNaseがコンタミしないように細心の注意をはらった。
Skin crushing Skin crushing was performed using a homogenizer AM-9 (Nippon Seiki) while freezing in liquid nitrogen. The inner surface of the cup touched by the sample and the cutter were sprayed with RNase detergent (RNaseZAP, Ambion) and then wiped with a Kim towel. Care was taken that liquid nitrogen was not in direct contact with the sample (so as not to be a source of contamination). In order to keep the sample cup at a low temperature during homogenization for about 30 minutes, liquid nitrogen was appropriately replenished. All homogenization operations were performed with vinyl gloves in a clean bench, and great care was taken to prevent RNase contamination.
IsogenとRNeasyミニカラム操作
皮膚粉末をエッペンドルフチューブに移し、Isogen（ニッポンジーン）1mlを加えたのち5分間かけてピペッティングとボルテックスによって充分攪拌した。クロロホルム0.2mlを加え15秒間ボルテックスで混合し2〜3分放置してから、4℃にて12,000rpmで15分間遠心分離した。水層（上層）を下層が混入しないように分取し、3/4倍量の75%エタノールを加え2本のRNeasyミニカラム（QIAGEN）で総RNAを精製した。RNeasyミニカラム操作はマニュアルに沿って実施したが、1本のRNeasyミニカラムにアプライするサンプル量が400μlを超えないよう、サンプル量が多い場合は2本のRNeasyミニカラムに分割した。
Isogen and RNeasy mini-column operation Skin powder was transferred to an Eppendorf tube, 1 ml of Isogen (Nippon Gene) was added, and the mixture was thoroughly stirred by pipetting and vortexing for 5 minutes. 0.2 ml of chloroform was added, mixed by vortexing for 15 seconds, allowed to stand for 2 to 3 minutes, and then centrifuged at 12,000 rpm for 15 minutes at 4 ° C. The aqueous layer (upper layer) was separated so that the lower layer was not mixed, 3/4 volume of 75% ethanol was added, and total RNA was purified with two RNeasy mini columns (QIAGEN). The RNeasy mini column operation was performed according to the manual, but when the sample amount was large, it was divided into two RNeasy mini columns so that the sample amount applied to one RNeasy mini column did not exceed 400 μl.
品質チェック
総RNAサンプルの品質を１本鎖を特異的に検出できるバイオアナライザーなどでチェックした。品質チェックはジーンフロンティア（株）、及びジーンフロンティア（株）が契約したNimbleGen Systems Iceland LLCに委託して実施した。品質基準値は、A260/280比＞1.7、A260/230比＞1.7、28S/18S＞1.0、総RNA量＞22μgなどであった。
Quality Check The quality of the total RNA sample was checked with a bioanalyzer that can specifically detect single strands. The quality check was commissioned to Gene Frontier Co., Ltd. and NimbleGen Systems Iceland LLC contracted by Gene Frontier Co., Ltd. Quality standard values were A260 / 280 ratio> 1.7, A260 / 230 ratio> 1.7, 28S / 18S> 1.0, total RNA amount> 22 μg, and the like.
フィッシュコラーゲンWP群6匹から得られた総RNAサンプルのうちの1サンプル、及びコントロール群6匹から得られた総RNAサンプルのうちの1サンプルの計2サンプルについて品質チェックを行なった。 A quality check was performed on a total of 2 samples, one sample of total RNA samples obtained from 6 fish collagen WP groups and 1 sample of total RNA samples obtained from 6 control groups.
cDNA合成とハイブリダイズ
総RNAを鋳型としてTTTTT-T7 primerを使って一本鎖 cDNAに逆転写した上で発光標識cDNAを合成した。ラットの21,205遺伝子のジーンチップは1遺伝子につき18の異なるプローブを装填していて、計21,205×18＝381,690種類のハイブリダイゼーションを行った。
cDNA Synthesis and Hybridization Luminescent labeled cDNA was synthesized after reverse transcription to single-stranded cDNA using TTTTT-T7 primer using total RNA as a template. The rat gene chip of 21,205 genes was loaded with 18 different probes per gene, and a total of 21,205 × 18 = 381,690 hybridizations were performed.
解析
ハイブリダイゼーションの結果は解析用ソフト“Nandemo Analysis 1.0.0”を用いて解析した。有意差検定は多重性をBonferroni法によって考慮し、有意水準を5%とした。つまり、21,205回の検定を繰返すことになるので、t検定p値に21,205を乗じたBonferroni p値を算出し、Bonferroni p値が0.05より小さい場合に有意な変化と判断した。
Analysis The hybridization results were analyzed using analysis software “Nandemo Analysis 1.0.0”. In the significance test, the multiplicity was considered by the Bonferroni method, and the significance level was set to 5%. That is, since 21,205 tests are repeated, a Bonferroni p value obtained by multiplying the t-test p value by 21,205 was calculated, and a significant change was determined when the Bonferroni p value was smaller than 0.05.
結果
コントロールに対するフィッシュコラーゲンWPの発現比が8倍超の6遺伝子、4倍超8倍以下の27遺伝子、2倍超4倍以下の97遺伝子、1.5倍超2倍以下の46遺伝子、1.5倍以下の21遺伝子が有意な増加を示した(多重比較)。有意に低下した遺伝子を含めると計266遺伝子が変動した（表３）。
表４にシスタチンの発現変動を、表５にシスタチン以外のタンパク質分解酵素の阻害因子の発現変動を示す。 Table 4 shows changes in expression of cystatin, and Table 5 shows changes in expression of inhibitors of proteolytic enzymes other than cystatin.
実施例２ コラーゲン投与によるシスタチンAの発現
動物の皮膚の抽出は、沸騰水中で1時間インキュベートした上でウルトラディスパーサーにて懸濁させた。タンパク質はWCA Protein Assay Kit（テクノケミカル）で定量した。
Example 2 Expression of Cystatin A by Collagen Extraction Animal skin was incubated in boiling water for 1 hour and then suspended in an ultradisperser. Protein was quantified with WCA Protein Assay Kit (Technochemical).
SDS-PAGE
電気泳動槽（TEFCO社 Model T. C.-803）に14% SDS-PAGE mini(1.0mm、8well、Cat No. 01-080M)を装着し、Laemmli R. Buffer(Tris 3.0g + Gly 14.4g + SDS 1.0g/1l)を泳動槽に満たした。メルカプトエタノールを含んだ2×サンプルバッファーと皮膚懸濁液を等量混和し、沸騰浴上で5分間変性させた上でウェル内にアプライした。一枚のSDS-PAGEの各ウェルのタンパク質量が14μgと一致するようにサンプル量を調整してアプライした。
SDS-PAGE
A 14% SDS-PAGE mini (1.0 mm, 8 well, Cat No. 01-080M) is attached to the electrophoresis tank (TEFCO Model TC-803), and Laemmli R. Buffer (Tris 3.0 g + Gly 14.4 g + SDS 1.0 g / 1l) was filled in the electrophoresis tank. An equal amount of 2 × sample buffer containing mercaptoethanol and skin suspension were mixed, denatured in a boiling bath for 5 minutes, and then applied to the wells. The sample amount was adjusted and applied so that the protein amount of each well of SDS-PAGE matched 14 μg.
分子量マーカーはPrecision Plus Protein Standards(Bio-Rad社 ＃161-0373)を、陽性対照は卵白シスタチン(Sigma社)10μgを用いた。変圧器はAE-3131(ATTO社)を用い10mAの定電流で泳動した。 As a molecular weight marker, Precision Plus Protein Standards (Bio-Rad # 161-0373) was used, and 10 μg of egg white cystatin (Sigma) was used as a positive control. The transformer was AE-3131 (ATTO) and migrated at a constant current of 10 mA.
ウエスタンブロティング
ウエスタンブロッティングはMini Trans-Blot Cell(Bio-Rad)にBlotting Buffer(Tris 25mM + Gly 192mM)を満たし、PVDFメンブレンへタンパク質をトランスファーした。変圧器はModel 200/2.0 Power Supply(Bio-Rad)を使い20mAで冷却下2時間ブロッティングした。
Western blotting In Western blotting, Mini Trans-Blot Cell (Bio-Rad) was filled with Blotting Buffer (
免疫反応
定法に従い、スキムミルク10%を溶解したTBS[Tris 20mM + NaCl 150mM + NaN3 0.05%(pH7.5)]にPVDF膜を浸漬し、（非特異吸着を抑えるため）常温で2時間ゆっくりと振倒した。
Immune reaction According to standard methods, immerse the PVDF membrane in TBS [Tris 20mM + NaCl 150mM + NaN 3 0.05% (pH7.5)] in which skim
Tween20 0.05%を溶解したTBS(TBS-T)で3回洗浄した後、抗シスタチンA抗体(ヒト由来 N末端ペプチドN-18でヤギを感作したポリクローナル抗体、Santa Cruz社 sc-33277)をゼラチン0.1%を溶解したTBSで1/200倍希釈し、（一次抗体として）常温で1時間ゆっくり振倒した。 After washing 3 times with TBS (TBS-T) containing 0.05% Tween20, anti-cystatin A antibody (polyclonal antibody sensitized with goat with human N-terminal peptide N-18, Santa Cruz sc-33277) The solution was diluted 1/200 times with 0.1% dissolved TBS and gently shaken at room temperature for 1 hour (as a primary antibody).
TBS-Tで3回洗浄した後、抗ヤギIgG抗体（免疫動物ロバ、アルカリフォスファターゼ標識、sc-2022）をゼラチン0.1%/TBSにて1/100,000倍希釈し、（二次抗体として）常温で1時間ゆっくり振倒した。 After washing 3 times with TBS-T, anti-goat IgG antibody (immune animal donkey, alkaline phosphatase labeled, sc-2022) was diluted 1 / 100,000 times with gelatin 0.1% / TBS (as a secondary antibody) at room temperature Shake slowly for 1 hour.
TBS-Tで3回洗浄した後、発色試薬（蒸留水24ml + 25×濃縮液 1ml + 試薬A 50μl + 試薬B 50μl、Bio-Rad社 ＃170-6432）に浸し発色させた。 After washing three times with TBS-T, the color was developed by soaking in a coloring reagent (distilled water 24 ml + 25 × concentrated liquid 1 ml + reagent A 50 μl + reagent B 50 μl, Bio-Rad # 170-6432).
解析
フィッシュコラーゲンWP群におけるシグナル面積をコントロール群のそれに対してt検定で評価した。
Analysis The signal area in the fish collagen WP group was evaluated by t test against that in the control group.
結果
11KDaの分子量を持ったシスタチンAのシグナルが確認され(図２、lane 2〜8)、その強度はコントロール(lane 6〜8)と比較してフィッシュコラーゲンWP摂取群(lane 3〜5)で強かった。
シスタチンAのシグナル面積は、コントロール群6.7±5.1mm2と比較してフィッシュコラーゲンWP摂取群で21.0±3.2mm2と3.1倍になった（図３）。
result
A signal of cystatin A having a molecular weight of 11 KDa was confirmed (Fig. 2, lanes 2-8), and its intensity was stronger in the fish collagen WP intake group (lanes 3-5) than in the control (lanes 6-8). It was.
Signal area of cystatin A became 21.0 ± 3.2 mm 2 and 3.1 times Fisshukoragen WP intake group compared with the control group 6.7 ± 5.1 mm 2 (Figure 3).
実施例３ コラーゲン投与による皮膚保水率の経時的変動
実施例２で用いた動物の皮膚保水率を測定した。
摂取開始（ゼロ点）、1週、2週、3週、4週、5週、6週、7週及び8週にコルネオメーター(インテグラル)を用いて左右の肩甲骨の中間部分の皮膚保水率を午前8〜9時に測定した。水分計の小型静電容量センサーをラット背部に押しあて3秒間静止して皮膚保水率をキャパシタンス値（単位無）で測定した。図４に結果を示す。
Example 3 Change in skin water retention rate with time by collagen administration The skin water retention rate of the animals used in Example 2 was measured.
Ingestion (zero point), 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks and 8 weeks using a Corneometer (Integral) to retain skin in the middle part of the left and right shoulder blades Rates were measured at 8-9 am. The moisture sensor's small capacitance sensor was pressed against the back of the rat and allowed to stand for 3 seconds, and the skin water retention rate was measured by the capacitance value (no unit). The results are shown in FIG.
実施例４ コラーゲン投与による皮膚保水率の改善
ヘアレスラット雄性HWY系（SPF、4週齢）を用い、飼育した。
様々な被験物質を5%となるようにラット用飼料CRF-1に配合した。試験飼料はオリエンタル酵母（株）に依頼して作成した（表１）。
群毎に各試験飼料を自由摂取させた。表６に群構成を示す。図５に試験プロトコールを示す。
Example 4 Improvement of Skin Water Retention Rate by Collagen Administration Hairless rat male HWY strain (SPF, 4 weeks old) was used for breeding.
Various test substances were added to the rat diet CRF-1 so as to be 5%. The test feed was prepared by requesting Oriental Yeast Co., Ltd. (Table 1).
Each group was given free access to each test feed. Table 6 shows the group structure. FIG. 5 shows the test protocol.
8週にコルネオメーター(インテグラル)を用いて左右の肩甲骨の中間部分の皮膚保水率を午前8〜9時に測定した。水分計の小型静電容量センサーをラット背部に押しあて3秒間静止して皮膚保水率を測定した。 The skin water retention rate of the middle part of the left and right scapula was measured at 8-9 am using a Corneometer (integral) at 8 weeks. The moisture meter was measured by pressing the moisture sensor's small capacitance sensor against the back of the rat and resting for 3 seconds.
動物の皮膚の抽出は、沸騰水中で1時間インキュベートした上でウルトラディスパーサーにて懸濁させた。タンパク質はWCA Protein Assay Kit（テクノケミカル）で定量した。シスタチンの発現は抗シスタチンA抗体(ヒト由来N末端ペプチドN-18で感作、Santa Cruz社 sc-33277)を用いたウエスタンブロッティング法で比較した。表７に被験物質が皮膚の保水率及びシスタチンAの発現に及ぼす影響を示す。 The animal skin was extracted by incubating in boiling water for 1 hour and then suspending with an ultradisperser. Protein was quantified with WCA Protein Assay Kit (Technochemical). Cystatin expression was compared by Western blotting using an anti-cystatin A antibody (sensitized with human-derived N-terminal peptide N-18, Santa Cruz sc-33277). Table 7 shows the effect of the test substance on the water retention rate of the skin and the expression of cystatin A.
表７よりフィッシュコラーゲンWP、豚皮由来コラーゲン、アボガドエキス及びメロンエキスは、何れも経口的に摂取することによって皮膚シスタチンの発現を高め、皮膚保水率が改善されることが判る。 From Table 7, it can be seen that fish collagen WP, pig skin-derived collagen, avocado extract and melon extract all increase the expression of skin cystatin and improve the skin water retention rate when taken orally.
実施例５ ヒトにおけるコラーゲンによる皮膚保水率の改善
（１）食品
日頃、慢性的に肌が乾燥し、肌荒れに悩んでいる20〜40歳台の健常な女性を対象に二重盲検並行群間比較試験を実施した。
試験は39名を無作為に3群に分割し、フィッシュコラーゲンWP含有飲料50ml（高用量8%、低用量4%）を8週間摂取させ、フィッシュコラーゲンWPを含まない対照飲料（プラセボ）50mlを摂取させる群と比較した。図６に結果を示す。
検討の結果、4週及び8週において、フィッシュコラーゲンWPの用量に依存して皮膚保水率が改善された。
Example 5 Improvement of skin water retention rate by collagen in humans (1) Food Double-blind parallel group for healthy women in their 20s to 40s who are chronically dry and suffer from rough skin A comparative test was conducted.
The test was randomly divided into 3 groups of 39 people, and 50 ml of fish collagen WP-containing beverage (8% high dose, 4% low dose) was ingested for 8 weeks, and 50 ml of control beverage (placebo) not containing fish collagen WP. Compared to the group to be ingested. The results are shown in FIG.
As a result of the examination, the skin water retention rate was improved depending on the dose of fish collagen WP at 4 weeks and 8 weeks.
（２）化粧品
表８に記載の原料６及び７を原料５と混和し、精製水40mlを加え、85℃に加温、攪拌し、溶解した後、室温まで冷却した。表８に記載の原料１〜４を混和、60℃に加温溶解し、精製水40ml中に攪拌下に添加し乳濁液を作成し、これに先に調製した水溶液を混和し、精製水を加え、全量を100mlとしてフィッシュコラーゲンWP 0.5%を含有したローションを得た。
表８にローションの組成を示す。
(2) Cosmetics The
Table 8 shows the composition of the lotion.
（３）医薬組成物
表９に記載の組成で、フィッシュコラーゲンWPを含有した経口投与用カプセルを作製した。
(3) Pharmaceutical composition With the composition shown in Table 9, capsules for oral administration containing fish collagen WP were prepared.
本発明のコラーゲン又は生体内でコラーゲン合成が促進されるコラーゲンの分解物又はコラーゲンのアミノ酸組成に近いアミノ酸組成物を有効成分として含むタンパク質分解酵素阻害因子発現増強剤、並びにシスタチン等のタンパク質分解酵素阻害因子は、皮膚の保水率を改善するための食品、医薬組成物及び化粧品として利用することができる。 Proteolytic enzyme inhibitor enhancement agent comprising as an active ingredient the collagen of the present invention or a collagen degradation product in which collagen synthesis is promoted in vivo or an amino acid composition close to the amino acid composition of collagen, and inhibition of proteolytic enzyme such as cystatin The factor can be used as a food, a pharmaceutical composition and a cosmetic for improving the water retention rate of the skin.
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